Dispensing lung contacting powdered medicaments

ABSTRACT

A combination aerosol container carrier and deceleration chamber carries an aerosol container in one configuration and in another dispenses powdered medicament from the aerosol container with inhaled particles predominantly below 10 microns in size at a low velocity which gives a comparatively high degree of topical effect in the lungs as compared with systemic effect from powders absorbed in the mouth. The lungs may be used as an effective administration route for systemic medicament effect.

United States Patent r191 Torgeson [451 May 7,1974

[ DISPENSING LUNG CONTACTING POWDERED MEDICAMENTS [75] Inventor: WilliamLee Torgeson, Minneapolis,

Minn.

[73] Assignee: American Cynamid Company,

Stamford, Conn.

[22] Filed: June 27, 1973 [21] Appl. No.: 374,176

[52] U.S. Cl.,..' 222/182, 128/203, 128/208,

- 222/4022 [51] Int. Cl .L A61m 15/02 [58] Field of Search... 222/182,183, 4022} [56] References Cited UNITED STATES PATENTS Meshberg 128/2033,559,851 2/1971 Steinman 222/222 Primary ExaminerRobert B. ReevesAssistant Examiner-Larry H. Martin Attorney, Agent, or FirmSamuel BranchWalker [57] ABSTRACT A combination aerosol container carrier anddeceleration chamber carries an aerosol container in one configurationand in another dispenses powdered medicament from the aerosol containerwith inhaled particles predominantly below 10 microns in size at a lowvelocity which gives a comparatively high degree of topical effect inthe lungs as compared with systemic effeet from powders .absorbed in themouth. The lungs may be used as an effective administration route forsystemic medicament effect.

3 Claims, 5 Drawing Figures PAIENTEMY 7 1974 SHEU 1 UP 2 IE. E

PATENTEDIAY new: 3.809.294

sum 2 or 2 DISPENSING LUNG CONTACTING POWDERED MEDICAMENTS BACKGROUND OFTHE INVENTION The inhalation of medicaments has long been known. Thereis a continuing effort to secure uniform comparatively accuratelymeasured dosages in selected areas. Large particles have a tendency tobe deposited in the mouth or upper throat. Small particles, below aboutmicrons, have a tendency to go deeper intothe lungs. The problem is tosecure the desired dose in the desired area of a desired medicament atthe desired time.

. Sometimes the systemic effect. of a drug on other or- SUMMARY OF THEINVENTION The present inventionis based upon the discovery that thedischarge from an aerosol container can be suspended in dry vaporizedpropellant mixed with air by theme of a deceleration chamber which isbig enough to serve as a carrier for the aerosol container in a storageand transportation configuration and which has a neckeddown mouthpieceat one end and a neckeddown spray system at the other.

The deceleration chamber is about the same volume as the human oralcavity, with the mouth open. It serves to decelerate the aerosol chargeto give a' low velocity to the dispersed powder, absorb the aerosol jetmomentum before the suspended powder enters the users mouth, completethe vaporization of the aerosol propellant, eliminating the possibilityof liquid propellant reaching the mouth, dilute, the propellant andsuspended powder with air, and give uniform and acceptable powderlosses, so that uniform doses are administered. It is desirable that amajor portion of a discharged medicament be administered to the user,but it is more important that each dose be of consistent and predictablesize and absorbability so that a known uniform dose is administered witheach actuation of the actuation button. A considerable percentage ofloss is acceptable if reliably uniform. With the present system, lossesof about 25 to 50 percent of the total medicament doses occur. Thedeceleration chamber traps much of the medicament that would deposit inthe mouth of the user, so that a relatively small amount of themedicament is deposited in the mouth as compared to the amount thatreaches the lungs, and is effective in the lungs.

Additionally, a trap system is used to submerge the metering valve toinsure that the metering valve is immersed in the propellant at alltimes so that the metering chamber does not drain and, in efiect, loseits prime. This at times is'referred to as a drain-free trap.

The system is. particularly adapted to the use of such drugs astriamcinolone acetonide and N,N-diethyl-4- methyl-l-piperazinecarboxamide pamoate(diethylcarbamazine pamoate), both of which are ofvalue in the treatment of asthma and both of which are desirablyadministered in small known uniform accurate dosages which are absorbedprimarily in the lung system as con- 2 trasted with the nose and throat.The physiological effectiveness is augmented by the possibility ofincreasing the concentration of drugs administered to the desiredlocation, as compared to that obtained when the drugs are administeredsystemically.

Some medicaments are conveniently administered by inhalation, for asystemic effect. Penicillin has been administered by inhalation,'as moreconvenient than by injection. Many drugs are absorbed through the lugs,if a suitable system of dispensing for inhalation is available. Theinhalation of gases, such as ether, or liquids is much more common.

DESCRIPTION OF THE PRIOR ART Certain representative patents in this verycrowded field include:

U. S. Pat. No. 2,533,065, Taplin and Bryan, Dec. 5, 1950,Micropulverized Therapeutic Agents shows the use of powdered penicillin,of a particle size of less than one micron, for inhalation therapy. Thepenicillin is disclosed as absorbed in the lungs with high efficiency.

U. S. Pat. Nos. 2,721,010, Meshberg, Oct. 18, 1955, Aerosol ContainersAnd Valves Therefor," and US. Pat. No. 2,968,427, Meshberg, Jan. 17,1961, Valve For Aerosol Container show metering valves for aerosolcontainer. Small uniform charges of the contents are dispensed on eachseparate actuation.

Such valves, among others, may be used for metering doses for thepresent invention.

U. S. Pat..No. 2,992,645, Fowler, July 18, 1961, Disperser.ForPowders,in Column 2 has a table showing the effect of particle size on the zoneof deposition of a powder in the respiratory tract. Powder sizes of 1and 3 microns are shown to go deeply into the lungs.

U. S. Pat. No. 3,012,555, Meshberg, Dispensing Package For Material.Under Pressure' shows an aerosol liquid dispenser with an operatingspray button assembled to the valve system, which button, with sprayorifice, fits removably into an applicator nozzle. In one configurationthe applicator nozzle is used for spray control; in another forprotective storage.

U. S. Pat. No. 3,219,533, Mullins, Nov. 23, 1965, Aerosol SolidMedicament In Propellant And Low- Level Ethanol Avoiding Higher-LevelEthanol Dis Aerosol Apparatus, shows an aerosol liquid dispenser usingcoaxial concentric extendable tubes for particle size control. The tubesin collapsed position function as a container carrier for storage. Inextended position, the mass of air in the tubes impedes the forward flowof a spray and serves as a partial barrier to the discharge jet. Theinside diameter is preferably 18 to 30 mm. and the length 3 to 10 timesthe diameter, preferably 5 to 7 times.

The aerosol container and valve are taken out of the stored position,and the valve stem is inserted into a dispensing spray head which formsthe end of the inner tube at the time of use.

Dec. '12, 1961,

Ramis teaches that for inhalation therapy, the particles of thetherapeutic agent should be between 0.5 and microns in size, sinceparticles above 5 microns may not reach the air-cells in the lungs whileparticles below 0.5 microns may fail to be deposited in the lungs. Ramisteaches using dichloro-difluoro-methane as the propellant in which theactive product is dissolved or kept in a homogeneous-emulsionsuspension. The disclosures are limited to soluble products. I

U. S. Pat. No. 3,727,806, Wilmot, Apr. 17, 1973, Valve Assembles ForAerosol Containers, shows a metering valve assembly in which a hollowmember fits over the inner end of the valve stem and moves therewith tocreate a capillary gap to aid in avoiding wastage as the containercontents become exhausted. This container is used in a valve downposition.

U. S. Pat. No. 2,467,895, Kushner and Brancone,. Apr. 19, 1949,Piperazine Derivatives and Method of 'Co., Rahway, N. J. 1968), pages1064 and 1065.

U. S. Pat, No. 3,457,350, Mallen, July 22, 1969, Method Of TreatingAsthma, shows the use of N,N- diethyl-4-methyl-l-piperazinecarboxamide(commonly called diethylcarbamazine) for asthma. The dihydrogen citratesalt is disclosed specifcally.

SUMMARY OF THE INVENTION A dispensing package for therapeuticagents'under pressure such as shown in Meshberg, US. Pat. No. 3,012,555,supra, is modified by adapting a valve to dispense a powdered medicamentsuspended in the propellant and discharging the nozzle into the entranceof a decelerationchamber having a cylindrical barrel portion, amouthpiece at the exit end, and container hOlder-tactuating buttonholder to hold the spray nozzle system.

Preferably, the deceleration and expansion chamber is adapted tocompletely enclose and hold the aerosol container during storage withthe system being assembled in one configuration for storage andtransportation and another for use. By having dust covers and sealingmeans, the assembly in storage and transportation position is protectedfrom contaminating dust and may be conveniently carried in the pocket ofa user and yet be rapidly assembled with minimum risk of contaminationof the contents at the time of use.

Because some medicaments may be used only under conditions of stress orat irregular hours, it is highly advantageous that the assembly becompletely protected in the storage and transportation configuration andreadily and rapidly convertible to the dose administering configurationwhen medicament is to be administered. 0

Other advantages will be appreciated by those skilled in the art fromthe detailed description of the device.

DRAWINGS FIG. 1 is a pictorial view of the aerosol dispenser assembledin dose administering configuration.

FIG. 2 is a view in partial section showing the dispenser in the storageand transportation configuration.

FIG. 3 is enlarged view in section showing the valve assembled to theexpansion chamber cover and particularly, an anti-drain tank to insurethat the metering valve is continuously immersed in the propellant and,thus, protected from partial draining and resulting irregular dosages.

FIG. 4 shows the same valve assembly in compressed position after a dosein which the valve stem has been depressed.

FIG. 5 is a second configurationin which the'actuating button fits intoa movable applicator nozzle for storage.

As shown in FIG. 1, the biggest element of the aerosol dispenser is thedeceleration chamber 11, preferably of a plastic such as polyethylene.The deceleration chamber has a cylindrical barrel 12 which convenientlymay be'about 2 94 inches in length and 1 A inches in internal diameterwith a shell wall thickness of around one-sixteenth inch. At one end isa mouthpiece 13 conveniently about seven-eighths inch in outsidediameter economical method of manufacture and a smooth, easily cleanableworking surface. A mouthpiece cap 15 fits removably on the mouthpiece indust excluding relationship. The cap may slide on either interiorly orexteriorly with a finger friction fit. The term finger friction fit isused to note a frictional relationship which will hold pieces togetherunder normalhandling conditions, but may be readily disengaged orengaged by finger pressure only. The exterior-surface of the mouthpiececap may be roughened or knurled for easier grasping by the fingers. Theedges of the mouthpiece cap and the mouthpiece may be broken" orslightly rounded in accordance with conventional practice for ease inassembly, as may other edges. Either the mouthpiece or the mouthpiececap may have small ribs of the order of' 0.002 inch to reduce frictionand ease engagement. By

having such small raised portions or beads on frictionally engagingportions, the natural resilience of plastic such as polyethylene isutilized to give a frictional engagement which may be readily disengagedwith the fingers without expensive requirements as to accuracy in sizingof the pieces. Similar assembly details may be used elsewhere. in thepresent dispenser, and are conventional in the plastics molding art.

At the open end of the cylindrical barrel 12 is a container holder 16.The container holder'is a multifunctional element. A holder flange 17fits across the open end of the cylindrical barrel 12. A positioningsleeve 18 engages the end of the cylindrical. barrel 12. Conveniently,but not necessarily, the positioning sleeve fits interiorly'of thecylindrical barrel 12 with a friction fit and the positioning sleeve islong enough to, prevent acv 5 cidental disengagement but permit readyremoval of the container holder 16. Conveniently, but not necessarily,the positioning sleeve 18 extends from the holder flange 17 so that itsresilience permits finger frictional engagement with the normal accuracyof molding parts. A containerholding sleeve 19 extends interiorly fromthe holder flange l7 and is of a size to fit around, retain, andposition an aerosol container 20. Conveniently, but not necessarily, theaerosol container 20 is of stainless steel or aluminum to hold highpressure aerosol propellants. The container holding sleeve is longenough and of a size to position and retain the aerosol containerassembly inside and axially of the deceleration chamber 11 duringstorage and transportation phases of using the device, and permits readydisengagement from the aerosol container 20 at the time ofadministration.

Through the holder flange extend one or more-air vents 21 which providefor the introduction of diluent air during use. Three vents, each/8111Ch diameter, give good results. V

Extending exteriorly from the holder flange 17 is a button holder 22.The button holder is hollow, has a closed end opposite to the holderflange, and has therein an indexing port 23 which is of a size and shapeto hold an aerosol actuating button 24, which is described in moredetail below. Because the aerosol actuating button is to be oriented,the shape of the indexing port 23 is such as to match with the actuatingbutton 24 and hold the actuating button in anoriented relationship. Asshown, the actuating button is cylindrical with a flat side 25 whichflatside cooperates with an indexing port flat 26 so that the spray isdirected axially of the deceleration chamber. Conveniently, but notnecessarily, the button holder is formed with two indexing ports 23 indiametrically opposed relationship so that the actuating button 24 canbe inserted from either side and the other port serves such as anadditional air inlet. At the end of the button holder 22 away from theholder flange 17 is a retaining bead 27 which conveniently extends upabout S/IOOOths of an inch above the exterior cylindrical surface of thebutton holder. A protective sleeve 28 fits in light frictionalengagement over and on the exterior surface of the button holder. Beingmade of plastic, there is sufficient resilience that the protectivesleeve 28 may be easily forced over the retaining head 27 into positionand is not readily removed so that it is retained in place during theuseful life of the dispenser. The protective sleeve has button apertures29 to permit the sleeve 28 to be rotated so that the button apertures 29index with the indexing ports and permit the button to be insertedtherethrough and yet can be rotated through about 90 to protect theassembly from the entrance of dust and dirt during storage andtransportation.

In FIG. 2 is shown the dispenser in the carrying configuration forstorage and transportation in which the container 20 is removed from thecontainer holding sleeve 19, the protective sleeve 28rotated until thebutton apertures 29 index with the indexing port 23, and assembled indose administering configuration by inserting the actuating button 24through the button aperture 29 into one of the indexing ports 13 so thatthe spray port 32 is axial and concentric with the cylindrical barrel 12of the deceleration chamber, so that the discharge from the aerosolcontainer is symmetrical with respect to the deceleration chamber.

As shown in FIG. 3, in the dose administering position the aerosolcontainer 20 extends upwards so that the medicament in propellant 33 isdrawn by gravity against the valve assembly 30.

The actuating button '24 has a spray port 32.which is convenientlycounterbored into the button and has a spray orifice 34 through whichthe medicament in propellant is discharged. This spray orifice mayeither be formed integral with the spray button or a separate metallicinsert may be used. Both are conventional constructions. The sprayorifice should have a diameter such that the discharged dose isdisbursed in finely divided form as a cone on exit from the sprayorifice.

An orifice of about 0.015 to 0.018 inch gives a good spray pattern. a

The actuating button- 24 fits snugly on the end of a valve stem 35 whichextends into the valve body 36. The valve body 36 has therein a meteringchamber 37 in which the valve stem 35 is slidably mounted. Between thevalve body and the ferrule 31 is a metering gasket 38 which performs thedual function of serving as a seal against loss of propellant when thevalve stem collar 39 presses against the metering gasket, and acts as aring seal around the valve stem 35 so that as the valve stem isdepressed against the valve spring 40, the metering port 41 in the valvestem passes the metering gasketand permits the contents of the meteringchamber to pass through the metering port 41, the axial valve stem bore42, extending throughthe valve stem, into the discharge passage 43 inthe actuating button'24 to the spray orifice 34. At the inner end of thevalve stem 35 are charging flutes 44. These cooperate with a charginggasket 45 which is held against the lower end of the metering chamber bya stainless steel valve stem washer 46 which, in turn, isheld againstthe bottom of the metering chamber 37 by the valve spring 40. Inoperation, as the valve stem 35 is depressed, the

' valve stem 35 passes through the charging gasket 45 so that thecharging flutes pass through the charging gasket and the full diameterof the valve stem 35 sealsagainst the charging gasket 45 so that themetering chamber is filled and closed at the inner end before themetering port 41 passes the metering gasket 38 which permits thecontents of the metering chamber to discharge through the. metering port41, the axial valve stem bore 42, the discharge passage 43, and thespray orifice 34.

FIG. 4 shows the actuating button 24 in depressed position with thevalve in the discharge position.

When pressure on the actuating button 24 is released, the valve stein 35is pushed outwardly by the valve spring 40 so that the metering port 41passes the metering gasket 38 which closes discharge from the meteringchamber, and later the charging flutes 44 pass the charging gasket 45permitting the propellant containing the medicament to flow through thecharging flutes 44 and again fill the metering chamber 37.

The valve body 36 a valve body flange 47 which covers the end of'theaerosol container 20 and is sealed thereto by a container gasket 48. Theferrule 31 holds the assemblyin position against the end of the aerosolcontainer 20 by the ferrule 31 being swaged against the stainless steelor aluminum aerosol container 20.

The above construction for a metering valve is one type of meteringvalve. Other conventional types of metering valves may be used.

Because the metering valve discharges a comparatively small charge; forinstance about 50 microliters per actuation is a convenient commercialsize, and each discharge has a volume of about that of a small drop ofwater, it is important that the metering chamber be completely filledbefore each actuation and that the metering chamber be prevented fromdraining back into the aerosol container between actuations. This lossof charge or loss of prime is prevented by an anti-drain tank 49. Theanti-drain tank 49 fits into a flange sleeve 50 on the valve body flange47 which flange sleeve 50 has an interior cylindrical surface againstwhich the anti-drain tank 49 is asnug friction fit. In the periphery ofthe anti-drain tank 49 and between the anti-drain tank and the flangesleeve 50 is a charging'passageSl which provides for refilling of theanti-drain tank from the main body of the medicament in propellant inthe aerosol container. 4 I

To protect against accidental disengagement of the anti-drain tank as,for example, by dropping the aerosol container on the floor during use,the anti-drain tank is sonically welded into position using anultrasonic seal in which ultrasonic energy is passed through the flangesleeve to the anti-drain tank. As the energy passes through, there is adiscontinuity between'the anti-drain tank and the flange sleeve so thatenergy is reflected and refracted causing dissipation of ultrasonicenergy which reappears as heat which melts and thereby seals theanti-drain tank to the flange sleeve. By such ultrasonic sealing, theassembly is economical and effective. When so sealed, the anti-draintankremains in position under any use or abuse that does not damage theaerosol container itself.

Because of the nature of the propellant composition, when the actuatingbutton is depressed with the aerosol container in dispensing position,the contents of the metering chamber are discharged and as the actuatingbutton is released, a new charge is drawn from the antidrain tank intothemetering chamber and the antidrain tank is refilled through thecharging passage 51.

The anti-drain tank remains filled with the propellant containing themedicament independent of the orientation of the aerosol container.Thus, a predictable, uniform, accurate dosage is dispensed with eachactuation of the actuating button. 1

By keeping the fluted end of the valve stem immersed in liquidpropellant at all times, the homogeneity of the solid finely dividedmedicament in the propellant is maintained more uniformly, and moreconsistent uniform doses are dispersed. The use of a plstic anti-draintank appears to aid in neutralizing electrical charges which wouldotherwise build up in the system. With a stainless steel aerosolcontainer 20, the periphery of the propellant charge is effectively at asingle potential, but the propellant can act as a dielectric so that theindividual particles of medicament become charged and affect theirdispersion and discharge-rate. With the an-' ti-drain tank, the effectof the stainless steel container is at least in part neutralized so thatstatic effects are reduced or minimized permitting more uniform chargecharacteristics. 7

In the absence of the anti-drain tank, the first 25 percent of dischargedoses are found to be higher than the last 25 percent so that the useris receiving more medi-, cation than anticipated from the new dispenserand less than anticipated from the nearly empty dispenser. With thepresent anti-drain tank, the variation in charges are minimized so thatthe user is obtaining a more reliably uniform dosage of the medicament.

It is difiicult to measure the effect of electrical charges within theaerosol container and in the deceleration chamber but independent of thetheoretical and scientific background for explaining uniformity ofcharge, it is found that with the present anti-drain tank, more uniformdosages are dispensed and with the deceleration chamber in which themouthpiece has less than half the cross sectional area of thecylindrical barrel, and the length of the cylindrical barrel is lessthan twice its diameter, the individual dosages of medicament inpropellant are dispersed into the deceleration chamber and lose the jetvelocity imparted by the propellant spray. If any particles still retainvelocity, they either impinge or are retained by the walls of thedeceleration chamber or are bounced away from the walls so that adispersed powder charge is formed which is mixed with additional diluentair and inhaled, as the user inhales the finely divided medicamentthrough the mouthpiece. A large portion of the medicament which wouldotherwise be deposited in'the mouth of the userand, hence, absorbedsystemically, are deposited on the walls of the deceleration chamber.

Even though the medicament may be fairly expensive, the dosages are sosmall that about a 25 to 50 percent loss in the deceleration chamber isa highly acceptable loss as compared with the advantages of consistencyand uniformity of the dose which is administered to the patient.

With many drugs it is veryimportant that the desired quantity beadministered to the user. Uniformity is important so that the physicianadministering knows what adjustments in dosage level need be madedepending on the response of the user.

In FIG. 5 is shown a modification of the aerosol dispenser system inwhich the container holding sleeve of the type shown in Meshberg, U.S.Pat..No. 3,012,555, supra, is used with an applicator nozzle 52 fittingin the holder flange 53 with the bottom end of the aerosol containerfitting into the applicator nozzle. Slidably fitting in the other end ofthe applicator nozzle is a button holding slide 54 which can be pressedinward for sealing or pulled'outward to hold the actuating button inoperating position. The details of this construction are shown in saidU.S. Pat. No. 3,012,555.

Other configurations can be used providing that the deceleration chamberis large enough to decelerate the dispensed aerosol charge and permitthe inhalation velocity from the inhalation of the user to be the solefactor in controlling the rate of administration at the time of use.With a metering trap holding about 50 microliters of material, theenergy of discharge is completely dissipated in the deceleration trapand a fine aerosol, almost a smoke, is formed of the drug to beadministered, and this fine aerosol is inhaled into the lungs.

A smoke is normally defined as a suspension of fine solid particles in agas such as may be produced by a fire with the particle sizes being inthe colloidal range. Here the particle sizes range from an overlap ofthe colloidal range at the small end to slightly larger than a truecolloid. The definitions as to particle size ranges are somewhatoverlapping.

For Applicants purpose, a particle size range from about 0.5 microns tomicrons gives good results. Particleslarger than about 10 microns aretoo apt to be deposited in the mouth or the throat of the user to bepreferred for inhalation therapy. A few particles in this size range areusually not deleterious, but contribute disproportionately to systemicabsorption rather than through the lungs.

In use, because part of the medicament deposits on the walls of thedeceleration chamber, the chamber sure propellant system is preferred.Dichlorodifluoromethane (Freon l2) which has a pressure'of about 80pounds per square inch absolute at room temperature gives good results.A stainless steel or aluminum container is preferred for such pressuresto avoid damage from breakage. Glass containers, or plastic containers,or a plastic covered and protected glass container may be used, butthese are more conventional at lower pressures, of theorder of 30 to 50pounds per square inch gage.

A plastic valve stem is preferred to metal, as the plastic valve stem'isless subject to binding or sticking from powder being packed around it.A small amount of a]- cohol, about 1 to 10 percent, functionsas alubricant to keep valve action reliable. Some medicament in propellantsystems function reliably without a lubricant.

Obviously, the size of the container and the size of the meteringchamber can vary widely depending upon the dosage desired'for actuation,and the number of 'doses desired to be given to a patient foradministration.

. Certain medicaments which may be effectively administered areillustrated by the following examples.

. EXAMPLE I DiethylcarbamazinePamoate Repetition of this procedure, withthe exception that the sodium pamoate is added as an aqueous solutionrather than a dry powder, results in the immediate precipitation of anamorphous solid that gradually crystallizes over a 2 day period. Thesolid is collected and air dried yielding 2.7 gm, M.P. 215220C. withdecomposition. Calculated: C, 67.44; H, 6.35; N, 7.15 Found: C, 66.90;H, 6.26; N, 7.05

EXAMPLE II Diethylcarbamazine Pamoate From Pamoic Acid y filteredthrough diatomaceous earth. The cake' is washed with three 2 literportions of methanol. The filtrate and washes are charged in a 100gallon glass lined kettle, 21 liters of water added, and 10.9 liters(130 moles) of concentrated hydrochloric acid is added fairly rapidly. Abright yellow solid precipitates immediately. Stirring is continued atroom temperature for l k hours. Free pamoic acid is recovered byfiltration and washed with three 20 liter portions of water. The cake isslurried with about 80 liters of water for 1 hour, solids filtered off,the solids washed with three 2 liter portions of water and then withthree 4 liter portions of methanol. The solid is then dried for 2 daysat 5055C. The crude pamoic acid (11.8 Kg.) is dis- 1 solved in 61 litersof dimethylformamide at 85-90C. Two pounds of diatomaceous earth areadded and the mixture is stirred for one-half hour before filtering,

through pre-heated funnels. The cake is washed with three 3 literportions of dimethylformamide. The filtrate is added to 70 liters ofwater in a 50 gallon glass lined kettle. An additional 20 liters ofwater is added and the resulting mixture is stirred for 1 12 hours whilebeing cooled to below 25C. The purified pamoic acid is filtered off,pressed dry and then washed with three 6 liter portions of waterfollowed by three 4 liter portions of methanol. The pamoic acid is driedto a constant weight of 10.8 Kg. 86 percent based on 95 percent realstarting disodium salt).

A l0.l Kg. (25.8 moles) portion of diethylcarbamazine dihydrogen citrateis dissolved in 80 liters of water and the solution is filtered.

A 1.96 Kg. (49.0 moles) portion of sodium hydroxide is dissolved in 100liters of water and 10.0 Kg. (25.8 moles) of purified pamoic acid,prepared as described in this example, is added. The pamoic acid-sodiumhydroxide mixture is stirred for one-half hour, -2 pounds ofdiatomaceous earth is added, stirring is continued for 1 hour and themixture is clarified by filtration.

The filtrate is charged in a gallon glass lined kettle, stirred and thediethylcarbamazine citrate solution is added as rapidly as convenient. Avery thick creamcolored precipitate forms immediately. Forty liters ofwater is added. After 1 hour of stirring thev mixture thins outconsiderably. Stirring is continued for l more hour. The product iscollected by filtration and washed with three 15 liter portions ofwater. The material is dried at 50-55C., and then micro-milled twice ina fluid energy mill to give 13.5 Kg. of product. A 10.8 Kg. portion ofthis diethylcarbamazine pamoate is dissolved in a mixture of 25 litersof dimethylsulfoxide and-50 liters of methanol at 65C. The hazy solutionis filtered through diatomaceous earth and the cake is washed with three4 liter portions of methanol. The filtrate and washes are charged in a50 gallon glass lined kettle and warmed to dissolve any separatedmaterial. Forty liters of methanol are added and the solution is chilledto and maintained at 0 (E4C. overnight. The product is fil rified pamoicacid in 400 ml of acetone heated to 50C.

there is added 53.0 gm (0.27 mole) of diethylcarbamazine dihydrogen'citrate. The resulting clear yellow solution is allowed to cool to roomtemperature and is then filtered. The filtrate is concentrated todryness in vacuo at 50C. and the resulting product is dried in vacuo at7580C. for 16 hours yielding 102.0 gm ofbis-(N,N-diethyl-4-methyl-l-piperazine carboxarnide) pamoate as a yellowamorphous powder, M.P. ll105C. Analysis: Calculated: C,65.62; H, 7.44;N, 10.68 C H N O (787) Found: C, 65.22; H, 7.79; N, 10.80

EXAMPLE IV N, N-diethyl-4-methyl-l-piperazinecarboxamide pamoate waspassed through a fluid energy pulverizing mill and micronized to 0.5 to10 microns, with 90 percent by weight being in the range of l to 5microns. 300 milligrams thereof in dry form where introduced into a 10milliliter stainless steel container adapted to be fitted with anaerosol metering spray nozzle, and thereto was added 0.75 grams ofanhydrous ethanol. Chilled (40C) dichlorodifluoro methane was added froma pressure tank to the open container which by evaporative coolingrapidly chilled the container and its contents, enough beingadded thatthe container held grams of dichlorofluoromethane, after which thecontainer was closed with a metering valve, and the metering valvesealed in place.

A metering valve was used which discharged 50 microliters of contentsper actuation which gives 1.3 milligrams ofN,N-diethyl-4-methyl-l-piperazinecarboxamide pamoate per actuation with65 milligrams of dichlorofluoromethane and 3.25 milligrams of ethanolbeing simultaneously dispensed. These are volatile and become mixedwith. enough air so as to have minimal or no physiological activity.

Depending upon the degree of severity of an asthmatic attack, one ormore actuations inhaled bring relief. The inhalation administrationgives a rapid and 'ef- Because the diethylcarbamazine pamoate isadminis- 6 tered directly to the lungs, a smaller dosage, as thediethylcarbamazine, is normally required for effective relief than ifadministered systemically, i.e., orally, with 12 I the circulator systembeing utilizedto carry the medicament to the lungs.

EXAMPLE V Triamcinolone acetonide Triamcinolone acetonide was micronizedin a fluid energy mill until percent by weight was in the particle sizerange of l to 5 microns.

A 19 ml. stainless steel container had charged thereto 30 mg. of themicronized triamcinolone acetonide, 0.244 ml. of anhydrous ethanol andwas cold filledwith 19.5 grams of dichlorodifluoromethane at 40C,evaporation serving to chill the container, and an excess being added toallow for evaporation. The filled containers were closed with a meteringvalve, as above described, and sealed. Dispersion in the propellant isimproved when the filled containers are immersed in an ultrasonic baththat transfers energy .from' the transducer to the contents of theaerosol container.

Good results are normally obtained by shaking to disperse thetriamcinolone acetonide in the system. Ultrasonic dispersal is arefinement to insure more uniform dispersion in micronized form. I

The components can be mixed, treated ultrasoni cally, and pressurefilled. Pressure f lling 'is more complex for small scale runs, butoften preferred for large size runs, and saves loss of the propellant.The valve needs to be specifically designed for such pressure fill.

Each actuation of the valve button delivers about 0.1 mg. oftriamcinolone acetonide. Five actuations four times a day gives a dosageof about 2 mg. of triamcinolone acetonide. As a portion is retained inthe deceleration chamber, and some is exhaled, slightly more than 1 mg.a day is administered for a typical patient. A systemic dose'for apatient is about 8 mg. The lower level and delivery to the preferredsite is a major'advantage.

The patient should be instructed to actuate the button to release themedicament into the deceleration chamber, and to inhale so that only theinspired air imparts velocity to the particles being absorbed. Thepatient should hold the inspired dose for a'few seconds to permitabsorption on lung surfaces before exhaling. A minor amount of themedicament is exhaled.

Wherein the propellant in the preceding example isdichlorodifluoromethane, other chlorofluoroalkanes and their mixturesmay be used.

Other modifications the art. I

I claim: a

1. An aerosol dispenser for dispensing uniform dosages of afinely-divided powdered medicament suspended in a propellant at a lowvelocity in inhalable dry aerosol form in the particle size range of 0.5to 10 microns, comprising a circular cylindrical container carrier anddeceleration chamber consisting essentially of a cylindrical barrel,and, at one end thereof, a mouthpiece and a mouthpiece-to-chamber flare,the mouthpiece being adapted to fit into a human mouth, said mouthpiecebeing cylindrical, and positioned coaxial with the cylindrical barrel bysaid flare,

a mouthpiece cap, adapted to removably engage and close the mouthpieceindust excluding relationship,

are apparent to those skilled in and at the other end of said chamber aremovable container holder, adapted to close the deceleration chamber inessentially air tight relationship, comprising a holder flange, adaptedto fit in sealing relationship with the cylindrical barrel of saidchamber, a container holding sleeve effectively coaxial and integralwith theholder flange and of a size to hold a circular the holderaerosol container with a friction-fit, and a button holder coaxial withthe holder flange with means to hold an actuating button on an aerosolcontainer in indexed relationship to discharge axially with thedeceleration chamber, in dose administering position,

means to close the button holding means in dust excluding relationshipin a carrier configuration,

and a circular cylindrical aerosol container having a 14 dose meteringvalve having thereon an actuating button, which button fits into saidbutton holding a means in a dispensing configuration and which containerfits interiorly of the cylindrical deceleration chamber in a storageconfiguration.

2. The aerosol dispenser of claim 1 in which the base of the aerosolcontainer fits into the container holding sleeve and the actuatingbutton extends towards and is shielded by the mouthpiece cap, when inthe storage and carrying configuration.

3. The aerosol dispenser of claim 1 in which the ferrule end of theaerosol container fits into the container holding sleeve, and theactuating button extends into the button holder, when in the storage andcarrying configuration.

Col.

Col. 1101.

I Col.-

Col. 001.

Patent No. 2 gnq pqu.

j UNITED STATES PATENT OFFICE-- 'CE'RTIFICATE 0F CORRECTION Dated May:7. 1974- Inventofls) wILLlAM LEE TORGESON It is certified that errorappears in the aboverident ified patent (SEAL) Attest: McCOY M. GIBSON.31%.; Arresting Officer and that said'Letters Patent are herebycorrected as shown below:

line 16, for "is" read if line 6,l for "holder" read holder -'--5 linefor "plsfic" read plastic linel'Z, for the first "The" I read To lineclose space between "N," andi-f'll".

1111a 1051 16" read 19 I line for "absorptioh" read adsorption line .7,for "theholder", read the holder line for "the holder" read cylindricalgned and sealed this 3rd day of December 1974 c. MARSHALL DANNITCommissioner of Pat ents F ORM PO-l 050 (10-69) 1 1 a I uscoMM-ocwan-bed Q .5. GQVIRIIIQI!" PRINTING OFFICE 2 Q. O-Sll-IJI'

1. An aerosol dispenser for dispensing uniform dosages of afinely-divided powdered medicament suspended in a propellant at a lowvelocity in inhalable dry aerosol form in the particle size range of 0.5to 10 microns, comprising a circular cylindrical container carrier anddeceleration chamber consisting essentially of a cylindrical barrel,and, at one end thereof, a mouthpiece and a mouthpiece-to-chamber flare,the mouthpiece being adapted to fit into a human mouth, said mouthpiecebeing cylindrical, and positioned coaxial with the cylindrical barrel bysaid flare, a mouthpiece cap, adapted to removably engage and close themouthpiece in dust excluding relationship, and at the other end of saidchamber a removable container holder, adapted to close the decelerationchamber in essentially air tight relationship, comprising a holderflange, adapted to fit in sealing relationship with the cylindricalbarrel of said chamber, a container holding sleeve effectively coaxialand integral with theholder flange and of a size to hold a circular theholder aerosol container with a frictionfit, and a button holder coaxialwith the holder flange with means to hold an actuating button on anaerosol container in indexed relationship to discharge axially with thedeceleration chamber, in dose administering position, means to close thebutton holding means in dust excluding relationship in a carrierconfiguration, and a circular cylindrical aerosol container having adose metering valve having thereon an actuating button, which buttonfits into said button holding means in a dispensing configuration andwhich container fits interiorly of the cylindrical deceleration chamberin a storage configuration.
 2. The aerosol dispenser of claim 1 in whichthe base of the aerosol container fits into the container holding sleeveand the actuating button extends towards and is shielded by themouthpiece cap, when in the storage and carrying configuration.
 3. Theaerosol dispenser of claim 1 in which the ferrule end of the aerosolcontainer fits into the container holding sleeve, and the actuatingbutton extends into the button holder, when in the storage and carryingconfiguration.